J Immunol. 2025 Apr 30:vkaf043. doi: 10.1093/jimmun/vkaf043. Online ahead of print.
ABSTRACT
Immunostimulants can be highly effective anti-cancer therapeutics; however, their systemic use is often limited by adverse reactions (AEs). Formulating immunostimulants into nanoparticle systems can potentially alleviate these, but nanoparticle design is key. In previous studies, we encountered anti-nanoparticle reactions with systemically administered PEGylated liposomes containing Toll-like receptor (TLR) agonists. In this work, we hypothesized that using a micellar drug delivery platform, rather than a liposomal platform, could retain the benefits of nanoparticle delivery systems while avoiding PEG recognition and generation of anti-PEG antibodies. Indeed, micellar formulation of the TLR7 agonist 1V270 induced far lower anti-PEG antibody levels and was well tolerated while retaining a similar circulation profile across multiple dosing. Furthermore, 1V270-micelles showed strong efficacy as monotherapy in murine syngeneic cancer models and showed combinatorial efficacy with anti-PD1 treatment. Following intravenous administration, tumors developed an inflammatory reaction and macroscopic hemorrhage 6 h post treatment followed by significant cell death 24 h post treatment, which was not observed in spleens and livers. Tumors displayed strong innate signaling within 24 h, which was accompanied by persistent massive infiltration of neutrophils and antigen-specific cytotoxic T cells, reduction in cancer cells and broad upregulation of immune-related genes. 1V270-micelles were well tolerated by non-human primates at doses equivalent to those displaying therapeutic activity in murine cancer models. Overall, the study provides novel insights into the mode of action of TLR7 agonists and demonstrates good and sustained tolerability of 1V270-micelles across animal models and excellent efficacy in murine cancer models by bridging innate and adaptive immunity.
PMID:40304584 | DOI:10.1093/jimmun/vkaf043